In this work we explored the mechanism of cAMP increase in Bullfrog sympathetic ganglia by a group of benzodiazepine analogues. Briefly, the positive findings are: 1) In Bullfrog sympathetic ganglia there are multiple forms of phosphodiesterase (PDE); 2) The pharmacologically active drugs inhibit PDE and do not change adenylate cyclase activity. The degree of inhibition is higher when PDE is activated by the endogenous protein activator. Most benzodiazepines have Ki value 10 to 40 times below the Km of PDE using cAMP as a substrate, whereas the Ki values are 2 to 60 times higher than the Km of PDE when cyclic 3',5' guanosine monophosphate (cGMP) is a substrate. This might explain the selective increase of cAMP but not cGMP by benzodiazepines. The increase of ganglionic cAMP by the benzodiazepines might be at least in part the mechanism by which these drugs modify synaptic transmission.